The goal for any formulation design of poorly soluble drugs is to increase the solubility. However, increased solubility is a challenge when the drug is administered to the oral cavity as rapidly dispersing or mucoadhesive buccal films. Most drugs are bitter and increased solubility may correlate with perceived worsening of the taste profile. The aim of the present work was to investigate the dual effect of inclusion complex formation, namely solubilization of two lipophilic model drugs (indomethacin and furosemide) in the hydrophobic cavity of hydroxypropyl-β-cyclodextrin with the aim of increasing the solubility in different electrolyte solutions, and at the same time hinder the taste sensation of the solubilized drug. Taste perception investigations were performed using an electronic tongue on simple solutions, inclusion complexes and on multi-component formulations such as orodispersible films and buccal films. The electrolyte media was found to have an effect on solubilization, association constant and complexation efficiency of both model drugs. Buffers containing phosphate ions were generally better than other electrolyte media with respect to the solubility parameters, and freeze-drying had a favorable effect on all the desirable properties. This work demonstrated that freeze-dried drug-hydropxypropyl-β-cyclodextrin complexes in solution, or added to orodispersible or buccal film, exhibit different taste sensation as compared to the plain drug in solution or reference films without complexes, indicating a successful taste-masking.

From a patient-centric perspective, oromucosal drug delivery is highly attractive due to the ease of administration without the need of swallowing, and improved patient safety. The aim of the presented work was to prepare a buccal film using a self-forming micellar drug solubiliser as the film matrix, combining it with a mucoadhesive polymer for an enhanced retention on the buccal mucosa. Specifically, we propose the use of a graft co-polymer (Soluplus®), as a solubiliser and film former, supplemented with polymers with more hydrophilic properties and known mucoadhesive properties; hydroxypropyl methylcellulose (HPMC) or modified hydroxypropyl pea starch (Lycoat®). The film was manufactured by the solvent casting method. The resulting dual polymer film containing HPMC exhibited resistance to erosion and mucoadhesive properties superior to the control films of single polymers. In an in vitro oral cavity model, these properties were shown to correlate with increased residence time on simulated oral mucosa. Furthermore, all films containing the graft co-polymer showed similar permeability characteristics of furosemide towards buccal TR146 epithelial cells. This work illustrated that it is possible to manufacture dry, solid, dual polymer films containing an advanced drug delivery system with a cheap and simple method. The combination of a graft co-polymer with a mucoadhesive polymer transform into drug solubilising micelles in a mucin-retentive hydrogel scaffold with longer retention time on buccal mucosa for safe and enhanced advanced formulation.

: In this study, self-assembling Soluplus® micelles were examined for inherent properties. Through calorimetric analysis, the critical micelle concentration (CMC) could be determined at 25 and 37 °C, and the influence of three media (Milli-Q water, phosphate-buffered saline (PBS) with a pH of 7.4 and 0.1 M HCl) on the lower critical solution temperature (LCST) was detected. Furthermore, the solubilisation of a poorly soluble drug, furosemide, into the Soluplus® micelles was studied. The concentration-dependent properties of the micellar system were assessed through an examination of the micellar size, polydispersity, morphology, viscosity and solubilising properties, which were all found to be affected by the concentration, but temperature, pH and the composition of the test medium were also found to have an effect. Homogeneity in the estimated micellar size and morphology was shown for monophasic micelle dispersions in lower concentrations and with a shift towards more complex structures or aggregates in higher concentrations. The micelles were further investigated in terms of drug release and biocompatibility with mucus-producing HT29-MTX cells, where no biocompatibility issues were found. In this research, the implications for oral drug delivery are discussed and valuable preformulation information is provided on the micellar properties of a Soluplus® drug system in a liquid or semi-solid form.

Oral candidiasis is an important opportunistic fungal infection and polyenes and azoles are still the most used antifungal agents. However, the oral absorption resulting from most available treatments is generally poor and, consequently, a very high frequency of administrations of antifungal agents is strongly required. Therefore, the major challenge is to improve the retention of the antifungal agents in buccal mucosa, and the encapsulation into mucoadhesive systems may be considered as a possible strategy to achieve this objective. Three types of mucoadhesive polymeric nanopartides (polylactic acid (PLA), polylactic-co-glycolic acid (PLGA) and alginate) were prepared using nystatin as model drug. The drug-loaded nanoparticles were then included in toothpaste, oral gel and oral films, respectively. The results demonstrated that the loaded nanoparticles were successfully produced, presenting a mean size between 300-900 nm and with a negative surface charge. Also, the determination of the encapsulation efficiency of all nanopartides showed values above 70%. In terms of the in vitro mucoadhesion, the best formulation was the oral film loaded with the PLGA nanoparticles followed by the oral gel with PLA nanoparticles and thirdly the toothpaste with alginate nanoparticles. This was confirmed in an in vitro rinsing model with mucus producing HT29-MTX cells, where the percentage of nystatin retained to the cells after 40 min of simulated saliva flow was between 10-27% when formulations were used and only 4% for free nystatin. Further studies will include in vivo testing using animal models.

Abstract Glycyrrhiza glabra L. is considered an important source of bioactive compounds. This study aimed at the development of an efficient solution for the treatment of oral candidiasis. Several extracts of Glycyrrhiza glabra L. were prepared using different solvents and their potential in vitro antifungal activity was assessed. Ethanolic extracts showed the most promising results against C. albicans. This extract was incorporated into mucoadhesive nanoparticles (PLA, PLGA and alginate), which were further included in an oral gel, an oral film and a toothpaste, respectively. The results showed that nanoparticles were successfully produced, presenting a mean size among 100–900 nm with high encapsulation efficiency. In vitro studies showed that the most bioadhesive formulation was the oral film with extract-loaded PLGA nanoparticles, followed by the toothpaste with extract-loaded alginate nanoparticles and the oral gel with extract-loaded PLA nanoparticles.

Oral candidiasis is an important opportunistic fungal infection and polyenes and azoles are still the most used antifungal agents. However, the oral absorption resulting from most available treatments is generally poor and, consequently, a very high frequency of administrations of antifungal agents is strongly required. Therefore, the major challenge is to improve the retention of the antifungal agents in buccal mucosa, and the encapsulation into mucoadhesive systems may be considered as a possible strategy to achieve this objective. Three types of mucoadhesive polymeric nanoparticles (polylactic acid (PLA), polylactic-co-glycolic acid (PLGA) and alginate) were prepared using nystatin as model drug. The drug-loaded nanoparticles were then included in toothpaste, oral gel and oral films, respectively. The results demonstrated that the loaded nanoparticles were successfully produced, presenting a mean size between 300–900 nm and with a negative surface charge. Also, the determination of the encapsulation efficiency of all nanoparticles showed values above 70%. In terms of the in vitro mucoadhesion, the best formulation was the oral film loaded with the PLGA nanoparticles followed by the oral gel with PLA nanoparticles and thirdly the toothpaste with alginate nanoparticles. This was confirmed in an in vitro rinsing model with mucus producing HT29-MTX cells, where the percentage of nystatin retained to the cells after 40 min of simulated saliva flow was between 10–27% when formulations were used and only 4% for free nystatin. Further studies will include in vivo testing using animal models. PAPER 2018

The present study is aimed to enhance the oral bioavailability of ketoprofen by inserting it into the matrix of poly(vinylpyrrolidone) (PVP) 1(10 spatially confined into microcontainers, by means of supercritical CO2-aided impregnation. Microcontainers are cylindrical reservoirs, with typical sizes in the micrometer range, with a cavity open on one side, where the drug formulation is loaded. Differently to traditional tablets, microcontainers have a higher surface area per unit volume, and release the drug only in one direction. This design is meant to enhance the absorption of problematic drugs, like those with poor solubility in water. In a previous study we introduced a novel technique for drug loading of microcontainers, based on inkjet printing and supercritical impregnation (SCI). We showed that SCI produces accurate and reproducible drug loading for large arrays of microcontainers. In the attempt of enhancing the throughput of the loading methods, we propose the replacement of polymer inkjet printing with an easier manual compression of the PVP powder into the microcontainers. As the second step, the polymer powder filled-microcontainers were submitted to SCI. The separate role of different impregnation parameters (temperature, pressure, time, drug concentration in the supercritical phase) was elucidated with respect to the loading capacity. The microcontainer filling was observed by means of optical macroimaging, Xray microtomography and scanning electron microscopy. The physical state of the drug was investigated by means of Raman spectroscopy and compared with selected representative PVP-ketoprofen physical mixtures. Finally, the drug loading was estimated by means of in vitro dissolution tests.The characterization study shows that the present loading method is a valuable alternative to the one previously described. The drug loading can be controlled with high accuracy and reproducibility and the impregnated drug is in amorphous state. These results demonstrate that SCI can be used as a high throughput loading technique for microfabricated devices for oral drug delivery. (C) 2015 The Authors. Published by Elsevier B.V.